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. 2006 Apr 5;12(3):320–328. doi: 10.1111/j.1750-3639.2002.tb00446.x

Delayed White Matter Injury in a Murine Model of Shaken Baby Syndrome

C Bonnier 1, B Mesplès 2, S Carpentier 1, D Henin 3, P Gressens 2,
PMCID: PMC8095820  PMID: 12146800

Abstract

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight‐day‐old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31‐day‐old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre‐treatment with the NMDA receptor antagonist MK‐801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.

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References

  • 1. Alexander RC, Sato Y, Smith W, Bennet T (1990) Incidence of impact trauma with cranial injuries ascribed to shaking. Am J Dis Child 144:724–726. [DOI] [PubMed] [Google Scholar]
  • 2. Barlow KM, Minns RA (2000) Annual incidence of shaken impact syndrome in young children. Lancet 356:1571–1572. [DOI] [PubMed] [Google Scholar]
  • 3. Bittigau P, Pohl D, Sifringer M, Stadthaus D, Ishimaru M, Shimizu H, Ikeda M, Lang D, Speer A, Olney JW, Ikonomidou C (1998) Modeling pediatric head trauma: Mechanisms of degeneration and potential strategies for neuroprotection. Restor Neurol Neurosci 13:11–23. [PubMed] [Google Scholar]
  • 4. Bittigau P, Sifringer M, Pohl D, Stadthaus D, Ishimaru M, Shimizu H, Ikeda M, Lang D, Speer A, Olney JW, Ikonomidou C (1999) Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 45:724–735. [DOI] [PubMed] [Google Scholar]
  • 5. Bonnier C, Nassogne MC, Evrard P (1995) Outcome and prognosis of whiplash shaken infant syndrome: late consequences after a symptom‐free interval. Dev Med Child Neurol 37:943–956. [DOI] [PubMed] [Google Scholar]
  • 6. Brown JK, Minns RA (1993) Non‐accidental head injury, with particular reference to whiplash shaking injury and medico‐legal aspects. Dev Med Child Neurol 35:849–869. [DOI] [PubMed] [Google Scholar]
  • 7. Bruce D, Alvai A, Bilaniuk L (1981) Diffuse cerebral swelling following head injuries in children: The syndrome of malignant brain edema. J Neurosurg 18:482–494. [DOI] [PubMed] [Google Scholar]
  • 8. Calder IM, Hill I, Scholtz CL (1998) Primary brain trauma in non‐accidental injury. J Clin Pathol 37:1095–1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Conway EE (1998) Nonaccidental Head Injury in Infants: “The shaken baby syndrome revisited.” Pediatric Ann 27:677–690. [DOI] [PubMed] [Google Scholar]
  • 10. Dias MS, Backstrom J, Falk M, Li V (1998) Serial radiography in the infant shaken impact syndrome. Pediatr Neurosurg 29:77–85. [DOI] [PubMed] [Google Scholar]
  • 11. Duhaime AC, Christian CW, Moss E, Seidl T (1996) Long‐term outcome in infants with the shaking impact syndrome. Pediatr Neurosurg 24:292–298. [DOI] [PubMed] [Google Scholar]
  • 12. Duhaime AC, Christian CW, Rorke LB, Zimmerman RA (1998) Nonaccidental head injury in infants—The shaken‐baby syndrome. New Engl J Med 338:1822–1829. [DOI] [PubMed] [Google Scholar]
  • 13. Frank Y, Zimmerman R, Leeds NMD (1985) Neurological manifestations in abused children who have been shaken. Dev Med Child Neurol 27:312–316. [DOI] [PubMed] [Google Scholar]
  • 14. Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982) Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12:564–574. [DOI] [PubMed] [Google Scholar]
  • 15. Graham DI, Raghupathi R, Saatman KE, Meaney D, McIntosch TK (2000) Tissue tears in the white matter after fluid percussion brain injury in the rat: relevance to human brain injury. Acta Neuropathol 99:117–124. [DOI] [PubMed] [Google Scholar]
  • 16. Geddes JF, Vowles GH, Hackshaw AK, Nickols CD, Scott IS, Whitwell HL (2001) Neuropathology of inflicted head injury in children. II. Microscopic brain injury in infants. Brain 124:1299–1306. [DOI] [PubMed] [Google Scholar]
  • 17. Haseler LJ, Phil M, Arcinue E, Danielsen ER, Bluml S, Ross BD (1997) Evidence from proton magnetic resonance spectroscopy for a metabolic cascade of neuronal damage in shaken baby syndrome. Pediatrics 99:4–14. [DOI] [PubMed] [Google Scholar]
  • 18. Ikonomidou C, Mosinger JL, Salles KS, Labruyere J, Olney JW (1989) Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to N‐methyl‐D‐aspartate neurotoxicity. J Neurosci 9:2809–2818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Ikonomidou C, Qin Y, Labruyere J, Kirby C, Olney JW (1996) Prevention of trauma‐induced neurodegeneration in infant rat brain. Pediatr Res 39:1020–1027. [DOI] [PubMed] [Google Scholar]
  • 20. Ikonomidou C, Turski L (1996) Prevention of trauma‐induced neurodegeneration in infant and adult rat brain: glutamate antagonists. Metab Brain Dis 11:125–141. [DOI] [PubMed] [Google Scholar]
  • 21. Innocenti GM (1995) Exuberant development of connections, and its possible permissive role in cortical evolution. Trends Neurosci 18:397–402. [DOI] [PubMed] [Google Scholar]
  • 22. Jaspan T, Narborough G, Punt JAG, Lowe J (1992) Cerebral contusional tears as marker of child abuse ‐ detection by cranial sonography. Pediatr Radiol 22:237–245. [DOI] [PubMed] [Google Scholar]
  • 23. Johnston MV, Jeon OM, Pevsner J, Blue ME, Naidu S (2001) Neurobiology of Rett syndrome: a genetic disorder of synapse development. Brain Dev 23: 206–213. [DOI] [PubMed] [Google Scholar]
  • 24. Marmarou A, Foda MAA‐E, van den Brink W, Campbell J, Kita H, Demethiadou K (1994) A new model of diffuse axonal injury in rats. Part I. Pathophysiology and biomechanics. J Neurosurg 80:291–300. [DOI] [PubMed] [Google Scholar]
  • 25. Marret S, Gressens P, Evrard P (1996) Arrest of neuronal migration by excitatory amino acids in hamster developing brain. Proc Natl Acad Sci 93:15463–15468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. McDonald JW, Johnston MV (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 15:41–70. [DOI] [PubMed] [Google Scholar]
  • 27. McIntosh TK, Smith DH, Meaney DF, Kotapka MJ, Gennarelli TA, Graham DI (1996) Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. Lab Invest 74:315–342. [PubMed] [Google Scholar]
  • 28. Oliver JE (1975) Microcephaly following baby battering and shaking. Br J Med 2:262–264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Ommaya AK, Faas F, Yarnell P (1968) Whiplash injury and brain damage: an experimental study. JAMA 204:285–289. [PubMed] [Google Scholar]
  • 30. Shaver EG, Duhaime AC, Curtis M, Gennarelli LM, Barret R (1996) Experimental acute subdural hematoma in infant piglets. Pediatr Neurosurg 25:123–129. [DOI] [PubMed] [Google Scholar]
  • 31. Sinal SH, Ball MR (1987) Head trauma due to child abuse: serial computerized tomography in diagnosis and management. South Med J 80:1505–1512. [DOI] [PubMed] [Google Scholar]
  • 32. Smith DH, Chen XH, Xu BN, McIntosh TK, Gennarelli TA, Meaney FD (1997) Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol Exp Neurol 56:822–834. [PubMed] [Google Scholar]
  • 33. Smith SL, Andrus PK, Gleason DD, Hall ED (1998) Infant rat model of the shaken baby syndrome: Preliminary characterization and evidence for the role of free radicals in cortical hemorrhaging and progressive neuronal degeneration. J Neurotrauma 15:693–715. [DOI] [PubMed] [Google Scholar]
  • 34. Tahraoui SL, Marret S, Bodenant C, Leroux P, Dommergues MA, Evrard P, Gressens P (2001) Central role of microglia in neonatal excitotoxic lesions of the murine periventricular white matter. Brain Pathol 11:56–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Vowles GH, Scholtz CL, Cameron JM (1987) Diffuse axonal injury in early infancy. J Clin Pathol 40:185–189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Zepp F, Brühl K, Zimmer B, Schumacher S (1992) Battered child syndrome: cerebral ultrasound and CT findings after vigourous shaking. Neuropediatrics 23:188–191. [DOI] [PubMed] [Google Scholar]
  • 37. Zimmerman RA, Bilaniuk LT, Bruce D, Schut I, Uzzell B, Goldberg HI (1979) Computed tomography of craniocerebral injury in the abused child. Neuroradiology 130:687–690. [DOI] [PubMed] [Google Scholar]

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